The invention relates to therapies for herpes virus infections in mammals.
Herpes Simplex 1 (HSV1), Herpes Simplex 2 (HSV2), Varicella-Zoster virus (VZV), and Epstein Barr virus (EBV) infections in humans are characterized by episodes of epithelial eruptions involving active virus production alternating with periods without clinical symptoms, i.e., in which the virus is in a latent state.
In the case of the herpes virus VZV, the initial acute infection is known as chicken pox, and reactivation from the subsequent latent infection is manifested as the disease shingles. Animal models of the latent state show that at some defined period following inoculation with virus, conventional homogenization techniques are unable to detect free virus, but that the presence of the vital genome can be demonstrated by explanation rescue (cocultivation) techniques (Price, Cancer Invest. 1985, 3:285-92, 389-403). In the mouse latency model for HSV1, viral genomes can be detected in sensory ganglia, most abundantly in trigeminal ganglia. The stimuli that cause virus to travel to neural cell bodies, the form of the viral genome present in the cells, and the molecular events that occur during reactivation of the virus are not known.
Development of antiherpetic drugs has focused on targeting inhibitors against the various enzymes encoded by the herpes viruses. Among virus-specific enzymes, the viral DNA polymerase has been an important target for nucleoside analogs such as acyclovir, bromovinyldeoxyuridine and DHPG.
HSVI, HSV2, VZV, and EBV are known to encode a thymidine kinase ("TK") enzyme in addition to the viral DNA polymerase. While the viral DNA polymerase is knownto catalyze the replication of the viral genome, the role(s) of the viral TKs are not well understood. The herpes virus TKs share homologies at the gene and amino acid sequence levels (summarized by Folkers et al., J. Computer-Aided Molec. Design, 5, 385-404 (1991)), and have common, though not identical, enzymatic properties. TK is not present simply to increase the pool of thymidine phosphates for viral DNA synthesis; mutant HSV1 strains deficient in TK activity replicate well in cell cultures and produce active infections in animals. Observations that TK.sup.- HSV mutants cannot produce latent, reactivatable infections in animals have led to the hypothesis that TK expression is required for the establishment or reactivation of virus from its latent state, particularly in tissues such as peripheral nerve ganglia where host TK expression and DNA synthesis are absent (Price, R. W. Cancer Invest. 1985, 3:285-92, 389-403).
Two major groups of TK inhibitors have been developed as potential herpesvirus therapeutics. The first are analogs of the substrate thymidine, involving modifications at the 5-position of the pyrimidine ring and/or the 5'-OH group of the sugar ring. The second group consists of guanine base and nucleoside analogs, including several 9-cycloalkylmethyl guanines in which TK inhibition and substrate properties have been separated, and a series of nonsubstrate derivatives with substituents on the exocyclic amino group of guanine.